Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. In this review, we aim to present the potential relationship between gut microbiota and the modulation of the immune system and the hypothetical implications in CRC treatment, namely ICIs. Precision medicine in cancer treatment could involve modulation of the microbiota through different strategies to improve tumor immunogenicity. Future data will help to better understand microbiota mechanisms and their role in ICI efficacy.
Hence, the microbiota may modulate the immune response, becoming a promising biomarker to identify patients who will benefit from ICIs. In addition, it has been described that gut microbiota influences tumor development and the host immune response. Therefore, ongoing studies investigate new approaches to convert “cold” to “hot” tumors in MSS/pMMR CRCs. Most CRCs display a molecular microsatellite stability/proficient DNA mismatch repair (MSS/pMMR) profile, so strategies to improve tumor immunogenicity are crucial. In fact, immunotherapy showed a remarkable antitumoral activity only on a small subset of CRC patients – the ones with microsatellite instability-high/deficient DNA mismatch repair (MSI-H/dMMR). Colorectal cancer (CRC) remains one of the most common and challenging cancer, but it is not traditionally considered a highly immunogenic tumor. The primary predictor of intrinsic immune resistance to ICIs is the absence of lymphocytes in the tumor, the so-called “cold tumors”. They induce a durable response in a wide variety of solid tumors, but this response depends on the infiltration of lymphocytes capable of recognizing and killing tumor cells. The treatment paradigm of neoplastic diseases has dramatically shifted with the introduction of immune checkpoint inhibitors (ICI). Furthermore, pembro provided a clinically meaningful improvement in PFS2 for patients with MSI-H/dMMR mCRC. Conclusions: Pembro provided a statistically significant improvement in PFS vs chemo as first-line therapy for patients with MSI-H/dMMR mCRC, with fewer TRAEs observed. HRQoL scores were improved with pembro vs chemo. There were no grade 5 TRAEs in the pembro arm and 1 grade 5 intestinal perforation in the chemo arm. Grade ≥3 treatment related adverse event (TRAE) rates were 22% vs 66% for pembro vs chemo. PFS2 was longer with pembro vs chemo (median not reached vs 23.5 mo ). Confirmed ORR was 43.8% vs 33.1% median (range) DOR was not reached (2.3+ to 41.4+) with pembro vs 10.6 mo (2.8 to 37.5+) with chemo. The 12- and 24-mo PFS rates were 55.3% and 48.3% with pembro vs 37.3% and 18.6% with chemo. Results: At data cutoff a total of 307 patients were randomized (153 to pembro, 154 to chemo).
Exploratory endpoints included duration of response (DOR), PFS2 (time from randomization to progression on next line of therapy or any cause death), and health-related quality of life (HRQoL). Secondary end points included ORR (RECIST v1.1, central review) and safety.
Primary end points were PFS (RECIST v1.1, central review) and OS. Patients receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Treatment continued until progression, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles (pembro only). Methods: Patients with locally-determined MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to first-line pembro 200 mg Q3W for up to 2 years or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab (chosen before randomization). We present results of the final PFS analysis and analysis of PFS2. Background: KEYNOTE-177 (NCT02563002) evaluated the antitumor activity of pembrolizumab (pembro) vs chemotherapy ± bevacizumab or cetuximab (chemo) as first-line therapy for patients with microsatellite-instability high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).
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